Several semi synthetic opioids are structurally related in that they only differ by virtue of the presence of a methoxy substituent, instead of a hydroxy substituent, on the aromatic ring of the phenanthrene. Such structurally related opiate compounds with a morphinan core include morphinone, codeinone, 14-hydroxymorphinone, 14-hydroxycodeinone, oxymorphone, oxycodone, hydromorphone and hydrocodone. These compounds can be prepared from starting materials such as morphine, codeine, oripavine and thebaine, or even from each other.
Traditionally, hydrocodone and hydromorphone have been synthesized in a two-step sequence from codeine and morphine: hydrogenation followed by an Oppenauer oxidation. The process is cumbersome and, for hydromorphone, low yielding. More recently hydrocodone and hydromorphone have been prepared from thebaine and oripavine respectively in a two-step sequence which includes a selective hydrogenation followed by hydrolysis of the resulting enol ether.
It is desirable to reduce the amount of the α,β-unsaturated ketone derivative (e.g. codeinone, morphinone) that is present in the final product, due to potentially adverse toxicological properties that can be associated with such derivatives. International patent applications nos. WO 2012/003468 and WO 2008/070658 and U.S. Pat. Nos. 7,674,800 and 7,851,482 disclose processes for producing opiates, such as oxymorphone, containing reduced amounts of the enone derivatives. However, these documents do not disclose the demethylation of opioids which contain a methoxy group.
H. Yajima, et al., J. Chem. Soc., Chem. Comm., 1974, 107, discusses the use of trifluoromethanesulfonic acid as a deprotecting reagent in peptide chemistry. However, there is no discussion of the need to avoid forming unwanted impurities, such as α,β-unsaturated ketone derivatives. It is important to minimise the formation of such impurities in these processes, particularly when the processes are involved in the formation of pharmaceutical substances for administration to patients.
U.S. Pat. No. 5,071,985 and J. D. Andre, et al., Synth. Comm., 22(16), 2313-2327 (1992) disclose processes for demethylating certain morphinan derivatives. However, there is no discussion of the need to minimise the formation of unwanted impurities, particularly α,β-unsaturated ketone derivatives.
The present invention addresses some of the problems associated with the processes of the prior art.
The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or common general knowledge.